Polycomb group (PcG) genes are known as negative regulators of the transcriptional memory mechanisms via chromatin silencing in Drosophila. They ensure the maintenance of transcription patterns of key regulators such as homeotic genes which were involved in the dictation of body plan, however the other functions and target genes were not well investigated to date. mel-18 is a mammalian homologue of Drosophila PcG gene posterior sex combs and encodes a transcriptional repressor with tumor suppressive activity. Here we found that mice overexpressing mel-18 showed a cell cycle arrest of mature B-cells on B-cell receptor (BCR) stimulation with downregulation of c-myc. Molecular analysis revealed that the downregulation of cyclinD2, cyclinE, CDK4, CDK6 , CDK7, and CDC25A causes the impaired activities of cyclin-dependent kinases, resulting in hypophosphorylation of the retinoblastoma protein. Vise versa, the upregulation of c-MYC, CDC25 and CDC2/CDK2 kinase activities resulted in augmentati
… Moreon of proliferation of B-cells in mel-18 deficient mice. c-Myc is known to regulate positively the expression of cdc25a. Thus we propose that mel-18 negatively regulates the cell cycle progression at least through a cascades leading to c-myc then cdc25a. We will also discuss that the defect in lymphocyte development of mel-18 deficient mice implies the involvement of mel-18 in the maintenance of immature lymphocyte by regulating their susceptibility to cell death. More recently we found the spontaneous tumorigenesis in aged mel-18+/- mice. Therefore we would like to propose that PcG genes are the regulators to control the balance between proliferation and cell deathin lympoid cell, hence in prospects of applications to prevention, diagnosis and therapy of immunological disease.現在までに、mel-18遺伝子が、(1)in vitroで、がん抑制遺伝子としての活性を持つこと、(2)c-myc遺伝子の発現を調節することにより、c-myc/cdc25カスケードを介してCyclin-CDK複合体の活性を制御し、細胞周期を調節していること、(3)さらにこのCDK活性調節を介して、RAG蛋白質(特にRAG2)の安定性を制御することでリンパ球の分化を制御していること(4)BCL-2ファミリーの発現調節を介して細胞死・細抱生存を制御していること、等を明らかにした。このPcG蛋白質複合体が、細胞内でどのような蛋白質と相互作用しているのか?またほかにどのような標的遺伝子を制御しているのか?細胞外からのどのようなシグナル伝達系によってPcGは制御されているのか?などの大問題にこれからアプローチする予定である。 Less